Project Summary Obesity is a major public health concern for which effective treatments are needed. The development of personalized and effective obesity treatment would benefit from an investigation into the individual differences underlying obesity susceptibility. In humans, predictors have focused on trait-based cognitive factors, but basic research in animals can evaluate the neural, hormonal, behavioral and energetic mechanisms that can?t be evaluated in humans. Variation in sensitivity to the food intake inhibitory effects of gastrointestinal (GI) satiation signals is one such factor contributing to these individual differences. Our novel preliminary data show that reduced behavioral sensitivity to the intake inhibitory effects of cholecystokinin (CCK), one of these GI signals, predicts greater high fat diet (HFD)-induced body weight (BW) gain. Additionally, rats with reduced behavioral sensitivity to the food intake inhibitory effects of CCK express reduced Fos immunoreactivity in the hindbrain nucleus tractus solitarius (NTS), that processes GI derived vagally communicated signals. Another predictor of obesity is short-term natural variation in BW. Novel preliminary work shows that greater day-to-day variation in BW predicts total HFD-induced BW gain. Based on exciting preliminary findings, the overall goal of this proposal is to investigate the physiological mechanisms underlying these two predictors of obesity. These proposed aims will test the hypothesis that individual differences in neural, behavioral and energetic energy balance regulatory mechanisms differentially predispose obesity. Specifically, we will investigate the contribution of vagally- mediated afferent satiation signaling to individual differences in behavioral sensitivity to the intake suppressive effects of CCK and subsequent HFD-induced BW gain (Aim 1), characterize the role of NTS neuronal activation in individual differences in CCK sensitivity and BW gain (Aim 2) and define the behavioral and energetic mechanisms underlying short-term BW variability that leads to increased BW gain (Aim 3). Together, the proposed aims will highlight the physiological mechanisms underlying these predictors of the susceptibility and individual differences in HFD-induced obesity.